1. WSB1 promotes tumor metastasis by inducing pVHL degradation
- Author
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Seo Yun Tong, Jong Min Lee, Jin Jen, Ping Yin, Jin Sung Jang, Bowen Gao, Tongzheng Liu, Haoxing Zhang, Liewei Wang, Jung Jin Kim, Debra Evans, Nicole D. Vincelette, Min Deng, Bo Qin, Jun Zhang, Sang Ah Han, Dong Wook Choi, Zhenkun Lou, Seung Baek Lee, Sang Yeop Yi, and Sun Hyun Kim
- Subjects
Proteasome Endopeptidase Complex ,medicine.medical_specialty ,Angiogenesis ,urologic and male genital diseases ,medicine.disease_cause ,law.invention ,Metastasis ,Ubiquitin ,Cell Movement ,law ,Cell Line, Tumor ,Neoplasms ,Internal medicine ,Genetics ,medicine ,Humans ,Neoplasm Invasiveness ,Neoplasm Metastasis ,Mutation ,biology ,Protein Stability ,Intracellular Signaling Peptides and Proteins ,Ubiquitination ,Proteins ,Cancer ,Hypoxia-Inducible Factor 1, alpha Subunit ,medicine.disease ,Cell Hypoxia ,female genital diseases and pregnancy complications ,Protein Structure, Tertiary ,Ubiquitin ligase ,Gene Expression Regulation, Neoplastic ,HEK293 Cells ,Endocrinology ,Von Hippel-Lindau Tumor Suppressor Protein ,Tumor progression ,biology.protein ,Cancer research ,Suppressor ,HT29 Cells ,Research Paper ,HeLa Cells ,Developmental Biology - Abstract
The von Hippel-Lindau tumor suppressor pVHL is an E3 ligase that targets hypoxia-inducible factors (HIFs). Mutation of VHL results in HIF up-regulation and contributes to processes related to tumor progression such as invasion, metastasis, and angiogenesis. However, very little is known with regard to post-transcriptional regulation of pVHL. Here we show that WD repeat and SOCS box-containing protein 1 (WSB1) is a negative regulator of pVHL through WSB1's E3 ligase activity. Mechanistically, WSB1 promotes pVHL ubiquitination and proteasomal degradation, thereby stabilizing HIF under both normoxic and hypoxic conditions. As a consequence, WSB1 up-regulates the expression of HIF-1α’s target genes and promotes cancer invasion and metastasis through its effect on pVHL. Consistent with this, WSB1 protein level negatively correlates with pVHL level and metastasis-free survival in clinical samples. This work reveals a new mechanism of pVHL's regulation by which cancer acquires invasiveness and metastatic tendency.
- Published
- 2015
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